The overall goal of this proposal is to evaluate the novel concept whether using lentiviral-engineered T cells that express T cell receptor (TCR) capable of recognizing hepatitis C (HCV)-induced liver tumor cells will improve efficacy of immunotherapy for this disease. Chronic infection with HCV can lead to several liver diseases including hepatocellular carcinoma and cirrhosis. These liver diseases are the major indication for liver transplantation. IFN-? in combination with ribavirin is used to treat HCV infections with limited success. In order to reduce the worldwide morbidity and mortality from HCV infection and HCV related diseases more effective treatments for HCV infected patients are necessary. In this proposal we will test the fundamental hypothesis that human T cells with redirected specificity for HCV associated liver tumor cells can be created by using lentiviral vector technology and can offer a clinically relevant and successful therapeutic approach. The ultimate goal is the development of a novel and improved therapy for hepatitis HCV related malignancy, a potentially major public health concerns with approximately 3% of the world's population. Lentiviral vectors (LVs) have been successfully evaluated in Phase l clinical trials in patients with HIV/AIDS, offering the possibility to more broadly apply this technology for the treatment of other diseases, including chronic infections and cancer. Lentigen's collaborator Dr. Michael Nishimura has helped pioneer adoptive immunotherapy as a potential therapeutic approach for hepatitis. Therefore, in Aim 1 of this proposal we will develop self inactivating (SIN) LVs expressing a and [unreadable] chains of the TCR capable of recognizing the HCV and/or liver tumor cells. In Aim 2, together with Dr. Nishimura's team, we will test safety and efficacy of LVTCR transduced T cells in preventing HCV- induced liver tumor growth and treating established tumors in vivo. In summary, Lentigen Corp. and Dr. Nishimura's laboratory are uniquely positioned to provide the first comprehensive evaluation of the redirected T cell approach to generate anti-HCV induced liver tumor effects in patients infected with HCV and to apply this in a future clinical trial for patients with this life threatening disease. [unreadable] [unreadable]